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Mechanisms of L-Cysteine Neurotoxicity

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Abstract

We review here the possible mechanisms of neuronal degeneration caused by L-cysteine, an odd excitotoxin. L-Cysteine lacks the omega carboxyl group required for excitotoxic actions via excitatory amino acid receptors, yet it evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and potentiates the Ca2+ influx evoked by NMDA. Both actions are prevented by NMDA antagonists. One target for cysteine effects is thus the NMDA receptor. The following mechanisms are discussed now: (1) possible increase in extracellular glutamate via release or inhibition of uptake/degradation, (2) generation of cysteine α-carbamate, a toxic analog of NMDA, (3) generation of toxic oxidized cysteine derivatives, (4) chelation of Zn2+ which blocks the NMDA receptor-ionophore, (5) direct interaction with the NMDA receptor redox site(s), (6) generation of free radicals, and (7) formation of S-nitrosocysteine. In addition to these, we describe another new alternative for cytotoxicity: (8) generation of the neurotoxic catecholamine derivative, 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac).

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REFERENCES

  1. Sagara, J., Miura, K., and Bannai, S. 1993. Maintenance of neuronal glutathione by glial cells. J. Neurochem. 61:1672-1676.

    Google Scholar 

  2. Kranich, O., Hamprecht, B., and Dringen, R. 1996. Different preferences in the utilization of amino acids for glutathione synthesis in cultured neurons and astroglial cells derived from rat brain. Neurosci. Lett. 219:211-214.

    Google Scholar 

  3. Dringen, R., Pfeiffer, B., and Hamprecht, B. 1999. Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J. Neurosci. 19:562-569.

    Google Scholar 

  4. Heafield, M. T., Fearn, S., Steventon, G. B., Waring, R. H., Williams, A. C., and Sturman, S. G. 1990. Plasma cysteine and sulphate levels in patients with motor neuron, Parkinson's and Alzheimer's disease. Neurosci. Lett. 110:216-220.

    Google Scholar 

  5. Miyamoto, M., Murphy, T. H., Schnaar, R. L., and Coyle, J. T. 1989. Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line. J. Pharmacol. Exp. Ther. 250:1132-1140.

    Google Scholar 

  6. Bradbury, M. W. B. and Deane, R. 1993. Permeability of the blood-brain barrier to lead. Neurotoxicology 14:131-136.

    Google Scholar 

  7. Keller, H. J., Do, K. Q., Zollinger, M., Winterhalter, K. H., and Cuénod, M. 1989. Cysteine: depolarization-induced release from rat brain in vitro. J. Neurochem. 52:1801-1806.

    Google Scholar 

  8. Zängerle, L., Cuénod, M., Winterhalter, K. H., and Do, K. Q. 1992. Screening of thiol compounds: depolarization-induced release of glutathione and cysteine from rat brain slices. J. Neurochem. 59:181-189.

    Google Scholar 

  9. Olney, J. W., Zorumski, C., Price, M. T., and Labruyere, J. 1990. L-Cysteine, a bicarbonate-sensitive endogenous excitotoxin. Science 248:596-599.

    Google Scholar 

  10. Karlsen, R. L., Grofova, I., Malthe-Sorenssen, D., and Fonnum, F. 1981. Morphological changes in rat brain induced by L-cysteine injection in newborn animals. Brain Res. 208:167-180.

    Google Scholar 

  11. Klingman, J. G. and Choi, D. W. 1989. Toxicity of sulphur-containing amino acids on cultured cortical neurones. Neurology 39:397-398.

    Google Scholar 

  12. Olney, J. W. and Ho, O. L. 1970. Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature 227:609-611.

    Google Scholar 

  13. Olney, J. W., Ho, O. L., Rhee, V., and Schainker, B. 1972. Cysteine-induced brain damage in infant and fetal rodents. Brain Res. 45:309-313.

    Google Scholar 

  14. Pedersen, O. O. and Karlsen, R. L. 1980. The toxic effect of L-cysteine on the rat retina. A morphological and biochemical study. Invest. Ophthalmol. Vis. Sci. 19:886-892.

    Google Scholar 

  15. Misra, C. H. 1989. Is a certain amount of cysteine prerequisite to produce brain damage in neonatal rats? Neurochem. Res. 14:253-257.

    Google Scholar 

  16. Olney, J. W. 1993. Role of excitotoxins in developmental neuropathology. APMIS 10 (Suppl. 40):103-112.

    Google Scholar 

  17. Sharpe, L. G., Olney, J. W., Ohlendorf, C., Lyss, A., Zimmerman, M., and Gale, B. 1975. Brain damage and associated behavioral deficits following the administration of L-cysteine to infant rats. Pharmacol. Biochem. Behav. 3:291-298.

    Google Scholar 

  18. Perry, T. L., Norman, M. G., Young, V. W., Whiting, S., Crichton, J. U., Hansen, S., and Kish, S. J. 1985. Hallervorden-Spatz disease: cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidums. Ann. Neurol. 18:482-489.

    Google Scholar 

  19. Lehmann, A., Hagberg, H., Orwar, O., and Sandberg, M. 1993. Cysteine sulphinate and cysteate: mediators of cysteine toxicity in the neonatal rat brain? Eur. J. Neurosci. 5:1398-1412.

    Google Scholar 

  20. Schurr, A., West, C. A., Heine, M. F., and Rigor, B. M. 1993. The neurotoxicity of sulfur-containing amino acids in energy-deprived rat hippocampal slices. Brain Res. 601:317-320.

    Google Scholar 

  21. Slivka, A. and Cohen, G. 1993. Brain ischemia markedly elevates levels of the neurotoxic amino acid, cysteine. Brain Res. 608:33-37.

    Google Scholar 

  22. Li, X, Wallin, C., Weber, S. G., and Sandberg, M. 1999. Net efflux of cysteine, glutathione and related metabolites from rat hippocampal slices during oxygen/glucose deprivation: dependence on γ-glutamyl transpeptidase. Brain Res. 815:81-88.

    Google Scholar 

  23. Madison, D. V., Malenka, R. C., and Nicoll, R. A., 1991. Mechanisms underlying long-term potentiation of synaptic transmission. Annu. Rev. Neurosci. 14:379-397.

    Google Scholar 

  24. Balázs, R. 1988. Metabolic imbalance and nerve cell damage in the brain. Prog. Brain Res. 73:447-461.

    Google Scholar 

  25. Choi, D. W. and Rothman, S. M. 1990. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13:171-182.

    Google Scholar 

  26. Rothman, S. M. and Olney, J. W. 1987. Excitotoxicity and the NMDA receptor. Trends Neurosci. 10:299-302.

    Google Scholar 

  27. Jesberger, J. A. and Richardson, J. S. 1991. Oxygen free radicals and brain dysfunction. Int. J. Neurosci. 57:1-17.

    Google Scholar 

  28. Choi, D. W. 1988. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623-634.

    Google Scholar 

  29. Mattson, M. P., Rydel, R. E., Lieberburg, I., and Smith-Swintosky, V. L. 1993. Altered calcium signaling and neuronal injury: stroke and Alzheimer's disease as examples. Ann. N.Y. Acad. Sci. 679:1-21.

    Google Scholar 

  30. Garthwaite, J., Charles, S. L., and Chess, W. R. 1988. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385-388.

    Google Scholar 

  31. Bredt, D. S., Hwang, P. M., and Snyder, S. H. 1990. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347:768-770.

    Google Scholar 

  32. Lipton, S. A. and Stamler, J. S. 1994. Actions of redox-related congeners of nitric oxide at the NMDA receptor. Neuropharmacology 33:1229-1233.

    Google Scholar 

  33. Puka-Sundvall, M., Eriksson, P., Nilsson, M., Sandberg, M., and Lehmann, A. 1995. Neurotoxicity of cysteine: interaction with glutamate. Brain Res. 705:65-70.

    Google Scholar 

  34. Pace, J. R., Martin, B. M., Paul, S. M., and Rogawski, M. A. 1992. High concentrations of neutral amino acids activate NMDA receptor currents in rat hippocampal neurons. Neurosci. Lett. 141:97-100.

    Google Scholar 

  35. Plaitakis, A., Smith, J., Mandel, J., and Yahr, M. D. 1988. Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet i:1015-1018.

    Google Scholar 

  36. Nath, K. A. and Salahudeen, A. K. 1993. Autooxidation of cysteine generates hydrogen peroxide: cytotoxicity and attenuation of pyruvate. Am. J. Physiol. 264:F306-F314.

    Google Scholar 

  37. D'Emilia, D. M. and Lipton, S. A. 1999. Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neurosci. Lett. 265:103-106.

    Google Scholar 

  38. Brorson, J. R. and Zhang, H. 1997. Disrupted [Ca2+]i homeostasis contributes to the toxicity of nitric oxide in cultured hippocampal neurons. J. Neurochem. 69:1882-1889.

    Google Scholar 

  39. Brorson, J. R., Sulit, R. A., and Zhang, H. 1997. Nitric oxide disrupts Ca2+homeostasis in hippocampal neurons. J. Neurochem. 68:95-105.

    Google Scholar 

  40. Lipton, S. A., Kim, W. K., Choi, Y. B., Kumar, S., D'Emilia, D. M., Raydu, P., Arnelle, D. R., and Stamler, J. S. 1997. Dual actions of homocysteine at the NMDA receptor. Proc. Natl. Acad. Sci. USA 94:5923-5928.

    Google Scholar 

  41. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., and Lipton, S. A. 1995. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92:7162-7166.

    Google Scholar 

  42. Lei, S. Z., Zhang, D., Abele, A. E., and Lipton, S. A. 1992. Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+prevents neurotoxicity. Brain Res. 598:196-202.

    Google Scholar 

  43. Lipton, S. A., Choi, Y.-B., Pan, Z.-H., Lei S. Z., Chen, H.-S. V., Sucher, N. J., Loscalzo, J., Singel, D. J., and Stamler, J. S. 1993. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626-632.

    Google Scholar 

  44. Colton, C. A., Pagan, F., Snell, J., Colton, J. S., Cummins, A., and Gilbert, D. L. 1995. Protection from oxidation enhances the survival of cultured mesencephalic neurons. Exp. Neurol. 132:54-61.

    Google Scholar 

  45. Ferkany, J. and Coyle, J. T. 1986. Heterogeneity of sodium-dependent excitatory amino acid uptake mechanisms in rat brain. J. Neurosci. Res. 16:491-503.

    Google Scholar 

  46. Gilman, S. C., Bonner, M. J., and Pellmar, T. C. 1994. Free radicals enhance basal release of D-[3H]aspartate from cerebral cortical synaptosomes. J. Neurochem. 62:1757-1763.

    Google Scholar 

  47. Volterra, A., Trotti, D., Tromba, C., Floridi, S., and Racagni, G. 1994. Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J. Neurosci. 14:2924-2932.

    Google Scholar 

  48. Taberner, P. V., Pearce, M. J., and Watkins, J. C. 1977. Inhibition of mouse brain glutamate decarboxylase by some structural analogues of L-glutamic acid. Biochem. Pharmacol. 26:345-349.

    Google Scholar 

  49. Aizenman, E., Lipton, S. A., and Loring, R. H., 1989. Selective modulation of NMDA responses by reduction and oxidation. Neuron 2:1257-1263.

    Google Scholar 

  50. Tang, L.-H. and Aizenman, E. 1993. Long-lasting modification of the N-methyl-D-aspartate receptor channel by a voltage-dependent sulfhydryl redox process. Mol. Pharmacol. 44:473-478.

    Google Scholar 

  51. Eimerl, S. and Schramm, M. 1992. An endogenous metal appears to regulate NMDA receptor mediated 45Ca2+influx and toxicity in cultured cerebellar granule cells. Neurosci. Lett. 137:198-202.

    Google Scholar 

  52. Eimerl, S. and Schramm, M. 1993 Potentiation of 45Ca uptake and acute toxicity mediated by the N-methyl-D-aspartate receptor: the effect of metal binding agents and transition metal ions. J. Neurochem. 61:518-525.

    Google Scholar 

  53. Hermann, A., Janáky, R., Dohovics, R., Saransaari, P., Oja, S. S., and Varga, V. 1999. Potentiation by L-cysteine of N-methyl-D-aspartate receptor: effects on intracellular free Ca2+in cultured cerebellar granule cells. Proc. West. Pharmacol. Soc. 42:25-26.

    Google Scholar 

  54. Olney, J. W., Misra, C. H., and deGubareff, T. 1975. Cysteine-Ssulfate: brain damaging metabolite in sulfite oxidase deficiency. J. Neuropath. Exp. Neurol. 34:167-176.

    Google Scholar 

  55. Olney, J. W., Ho, O. L., and Rhee, V. 1971. Cytotoxic effects of acidic and sulphur-containing amino acids on the infant mouse central nervous system. Exp. Brain Res. 14:61-76.

    Google Scholar 

  56. Patneau, D. K. and Mayer, M. L. 1990. Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J. Neurosci. 10:2385-2399.

    Google Scholar 

  57. Porter, R. H. P. and Roberts, P. J. 1993. Glutamate metabotropic receptor activation in neonatal rat cerebral cortex by sulphur-containing excitatory amino acids. Neurosci. Lett. 154:78-80.

    Google Scholar 

  58. Griffiths, R. 1990. Cysteine sulphinate (CSA) as an excitatory amino acid transmitter candidate in the mammalian central nervous system. Prog. Neurobiol. 35:313-323.

    Google Scholar 

  59. Griffiths, R., Malcolm, C., Ritchie, L., Frandsen, A., Schousboe, A., Scott, M., Rumsby, P., and Meredith, C. 1997. Association of c-fos mRNA expression and excitotoxicity in primary cultures of mouse neocortical and cerebellar neurons. J. Neurosci. Res. 48:533-542.

    Google Scholar 

  60. Griffiths, R., Grieve, A., Dunlop, J., Damgaard, I., Fosmark, D., and Schousboe, A. 1989. Inhibition by excitatory sulphur amino acids of the high-affinity L-glutamate transporter in synaptosomes and in primary cultures of cortical astrocytes and cerebellar neurons. Neurochem. Res. 14:313-323.

    Google Scholar 

  61. Boss, V., Nutt, K. M., and Conn, P. J. 1994. L-Cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity. Mol. Pharmacol. 45:1177-1182.

    Google Scholar 

  62. Watkins, J. C. 1978. Excitatory amino acids. Pages 37-69, in McGeer, E. G. (ed.), Kainic Acid as a Tool in Neurobiology, Raven, New York

    Google Scholar 

  63. Andiné, P., Orwar, O., Jacobson, I., Sandberg, M., and Hagberg, H. 1991. Extracellular acidic sulfur-containing amino acids and gamma-glutamyl peptides in global ischemia: postischemic recovery of neuronal activity is paralleled by a tetrodotoxin-sensitive increase in cysteine sulfinate in the CA1 of the rat hippocampus. J. Neurochem. 57:230-236.

    Google Scholar 

  64. Nunn, P. B., Davis, A. J., and O'Brien, P. 1991. Carbamate formation and the neurotoxicity of L-α-amino acids. Science 251:1619.

    Google Scholar 

  65. Max, B. 1991. This and that: the neurotoxicity of carbon dioxide. Trends Pharmacol. Sci. 12:408-411.

    Google Scholar 

  66. Alagarsamy, S., Philips, M., Pappas, T., and Johnson, K. M. 1997. Dopamine neurotoxicity in cortical neurons. Drug Alcohol Depend. 48:105-111.

    Google Scholar 

  67. Cheng, N., Maeda, T., Kume, T., Kaneko, S., Kochiyama, H., Akaike, A., Goshima, Y., and Misu, Y. 1996. Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons. Brain Res. 743:278-283.

    Google Scholar 

  68. Noh, J. S., Kim, E. Y., Kang, J. S., Kim, H. R., Oh, Y. J., and Gwag, B. J. 1999. Neurotoxic and neuroprotective actions of catecholamines in cortical neurons. Exp. Neurol. 159:217-224.

    Google Scholar 

  69. Montine, T. J., Picklo, M. J., Amarnath, V., Whetsell, W. O. Jr., and Graham, D. G. 1997. Neurotoxicity of endogenous cysteinyl-catechols. Exp. Neurol. 148:26-33.

    Google Scholar 

  70. Hoyt, K. R., Reynolds, I. J., and Hastings, T. G. 1997. Mechanisms of dopamine-induced cell death in cultured rat forebrain neurons: interactions with and differences from glutamate-induced cell death. Exp. Neurol. 143:269-281.

    Google Scholar 

  71. Greenamyre, J. T. and O'Brien, C. F. 1991. N-Methyl-D-aspartate antagonists in the treatment of Parkinson's disease. Arch. Neurol. 48:977-981.

    Google Scholar 

  72. Han, J., Cheng, F.-C., Yang, Z., and Dryhurst, G. 1999. Inhibitors of mitochondrial respiration, iron (II), and hydroxyl radical evoke release and extracellular hydrolysis of glutathione in rat striatum and substantia nigra: potential implications to Parkinson's disease. J. Neurochem. 73:1683-1695.

    Google Scholar 

  73. Li, H. and Dryhurst, G. 1997. Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson's disease. J. Neurochem. 69:1530-1541.

    Google Scholar 

  74. Li, H., Shen, X.-M., and Dryhurst, G. 1998. Brain mitochondria catalyze the oxidation of 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1) to intermediates that irreversibly inhibit complex I and scavenge glutathione: potential relevance to the pathogenesis of Parkinson's disease. J. Neurochem. 71:2049-2062.

    Google Scholar 

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Authors and Affiliations

  1. Brain Research Center, Medical School, University of Tampere, Finland

    R. Janáky, V. Varga, A. Hermann, P. Saransaari & S. S. Oja

  2. Department of Animal Anatomy and Physiology, University of Debrecen, Hungary

    V. Varga & A. Hermann

  3. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland

    S. S. Oja

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Janáky, R., Varga, V., Hermann, A. et al. Mechanisms of L-Cysteine Neurotoxicity. Neurochem Res 25, 1397–1405 (2000). https://doi.org/10.1023/A:1007616817499

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